Regulating forces at the nuclear envelope to protect against cancer

Cancer metastasis accounts for most cancer-related deaths. To invade surrounding tissues, cancer cells need to migrate through dense and constricted spaces, which results in high mechanical stress on the nucleus, a large and stiff organelle. This can lead to nuclear envelope ruptures during interphase (NERDI), the transient mixing of cytoplasmic and nuclear contents and, in turn, DNA damage. Although NERDIs are rapidly repaired, the acquired DNA damage causes genome instability, further enhancing the cell’s metastatic potential.
Recent studies have identified the endosomal sorting complex required for transport (ESCRT) machinery as a key membrane remodelling pathway required for nuclear envelope (NE) resealing after NERDI. Importantly, we have shown that BROX, an ESCRT-associated protein, promotes the relaxation of cytoskeleton-mediated compressive forces on the nuclear surface, thereby facilitating efficient membrane resealing and protecting the genome from damage. Critically haploinsufficiency in the BROX gene has been associated with hereditary thyroid cancer, suggesting that mechanical dysregulation at the NE may act as a novel oncogenic mechanism.
In this project we will explore whether mechanoregulation at the NE is disturbed in cells bearing BROX mutations found in thyroid cancer. Gene editing will be used to generate cell lines expressing the relevant BROX variants. The effect of these variants in NERDI repair and genomic stability will be determined by cutting edge microscopy. Biophysical techniques, such as atomic force microscopy, will be performed in collaboration with the Physics department to determine the mechanical properties of the NE in these cells.